Antigen-specific immunotherapies have long been pursued for acute myeloid leukemia (AML). So far most exploited are antibodies targeting the membrane-distal V-set domain of CD33, a glycoprotein displayed on the cell surface of leukemic blasts in almost all cases and possibly leukemia stem cells in some. Improved survival of some patients with gemtuzumab ozogamicin validates this approach but many patients with CD33+ AML do not benefit from this antibody-drug conjugate, prompting interest in developing improved CD33-directed therapeutics. Because AML cells are exquisitely radiosensitive across the entire genetic disease spectrum, a- emitting radionuclides are ideal to arm anti-CD33 antibodies. Unlike b-emitters, they deliver a very high amount of radiation over just a few cell diameters, thereby enabling precise and efficient target cell kill (as few as 10 a- particle hits are sufficient to kill a malignant hematopoietic cell). Early clinical trials with an anti-CD33 antibody labeled with actinium-225 (225Ac-lintuzumab) have been conducted. Besides high cost, however, important shortcomings include the long half-life of 225Ac, leading to freely circulating radionuclide if not retained effectively in target cells, and the release of daughter radionuclides after decay of 225Ac with risk of associated toxicity to healthy tissues. We hypothesize that labeling with astatine-211 (211At), an a-emitter we have focused on because of its shorter half-life and because it decays without production of any long-lived or potentially dangerous daughter isotopes, will provide a novel, superior form of CD33-directed radioimmunotherapy (RIT). Using humanized mice, we have recently generated a panel of fully human antibodies recognizing either the V-set domain or, as the first group, the membrane-proximal C2-set domain of human CD33. Since the V-set but not C2-set domain is missing in some CD33 variants, C2-set domain-directed antibodies can recognize all naturally- occurring variants of CD33 (i.e. are ?CD33PAN antibodies?). With these antibodies available, we now plan to optimize CD33-directed RIT for application in AML patients, focusing on 211At. To accomplish this task, we have assembled a multidisciplinary team of investigators with complementary expertise in developing radioimmunoconjugates and other antibody-based therapeutics for AML. Envisioning broad use, we will study 211At-CD33 RIT as ?stand-alone? therapy and as augmentation of HCT conditioning, focusing on MHC- haploidentical in vivo models AML. Since many HCT candidates do not have an HLA-matched donor, facilitation of alternative donor HCT remains a critical unmet need, particularly for the extension of this lifesaving option to patients from ethnic minority groups. We expect results from our studies will be readily translatable into the clinic and are anticipated to have an important positive impact as they will provide the groundwork for a new treatment option for patients with AML and other CD33+ neoplasms, for whom current treatment outcomes are unsatisfactory.